Kappa opioid receptors (KORs) are present in the brain, spinal cord, and on the central and peripheral terminals and cell bodies of the primary sensory afferents (somatic and visceral), as well as on immune cells.
KORs which are located in the brain have been shown to mediate the central analgesic effects of molecules, commonly referred to as kappa agonists, which activate such KORs. This finding led to numerous attempts (i.e. Spiradoline from Upjohn and Enadoline from Parke-Davis) to develop brain-penetrating, non-peptidic kappa agonists for use as original analgesics which would be devoid of the unwanted side effects (constipation, respiratory depression, dependence and addiction) of morphinic analogs that act on mu opioid receptors (MORs). The analgesic activity, as well as the lack of mu-opioid side effects, of this class of compounds has been established both in animals and humans. However, some systemic kappa agonists were also shown to induce specific side effects such as diuresis, sedation and dysphoria, mediated through kappa receptors located in the brain, which resulted in the discontinuation of their development.
In addition to such centrally mediated analgesia, stimulation of KORs located either in the periphery or in the spinal cord may also produce analgesia. However, neither peripheral nor spinal KORs were associated with any of the side effects of systemic kappa agonists. Therefore, as long as it is possible to create kappa receptor opioid agonists that do not enter the brain (following either peripheral or spinal administration), it should be possible to obtain safe and original analgesics.
It is now considered that peptidic opioid agonists that are selective for the KOR should be ideal for this purpose because they are likely, at the most, to only poorly enter the brain after either peripheral or spinal administration; therefore, they are expected to be devoid of central side effects. Parenteral (i.v., i.m., s.c. epidural, topical or local) routes of administration may thus be suitable for this class of compounds to treat pain in conditions associated with inflammation, such as rheumatoid arthritis, or post-operative pain, such as that resulting from eye surgery, dental surgery, articulation surgery, abdominal surgery, childbirth and cesarian section. Furthermore, alleviation of abdominal postsurgery symptoms (digestive ileus) is presently considered to be a major therapeutic target of peptidic kappa agonists. These symptoms include motility disorders such as bloating, nausea, and intestinal transit inhibitions associated with sensitivity disorders, such as pain possibly induced by distension. Such motor disturbances are considered to be the consequence of a prior alteration of visceral sensitivity resulting from nerve sensitization by local inflammatory process, and it has been shown in animal models that compounds which block pain may also reverse motor impairments (Riviere et al., Gastroenterology, 104:724-731, 1993). Indeed, non-peptidic kappa agonists were shown to produce antinociception in experimental ileus that was associated with a restoration of normal motor functions. Such provides a rationale for developing nonbrain-penetrating kappa agonists for treatment of post-operative pain and digestive ileus (Friese et al., Life Sciences, 60(9):625-634, 1997). Because such kappa agonists generally do not exhibit a constipating or antitransit side effect, they have a major advantage for this indication compared to morphine-like compounds.
It has also been shown that kappa agonists produce peripheral antinociception in models of intestinal as well as colonic hyperalgesia induced by mild and local inflammation (Diop et al., Eur. J. Pharm., 271:65-71, 1994). As a result, Irritable Bowel Syndrome (IBS), which includes exaggerated visceral pain due to a visceral hypersensitivity possibly linked to a local inflammation, is also a target for a peripheral kappa agonist (Junien and Riviere, Alimentary Pharmacology and Therapeutics, 9:117-126, 1995).
In addition to the gastrointestinal tract, other viscera showing a pathological condition that involves activation and/or sensitization (i.e. local inflammation) of primary sensory afferents are also considered to represent appropriate targets for such a kappa receptor opioid. Examples of these conditions where kappa receptor opioids can be used include urinary incontinence due to bladder inflammation (cystitis), dysmennorhea, vasomotor rhinitis, ocular inflammation, and kidney or bladder stone-induced pain.
It was established in somatic tissues that kappa agonists also block neurogenic inflammation by inhibiting the release of substance P from primary sensory afferents. Assuming such activity is also present in GI and visceral tissues, peripheral kappa agonists would be expected to have an ameliorating effect in conditions where pain or visceral hypersensitivity is associated with neurogenic inflammation (e.g. bladder cystitis).
Kappa opioid agonists are also known to act on the immune system and have primarily an inhibitory role on immune cells. Their effects include (i) suppression of T cell-dependent antibody production, (ii) alteration of mitogen- and antigen-induced lymphocyte proliferation, (iii) modulation of natural killer (NK) cell- and T cell-mediated cytotoxicity; (iv) chemotaxis of peripheral blood derived mononuclear cells (PBMC), and (v) alteration of PMBC function. These effects might be of interest in some specific indications, where it is important to lower the immune response.
Peptides which will not enter the brain, which exhibit high affinity for the KOR versus the MOR, which have high potency and efficacy, and which exhibit long duration of action in vivo are particularly desired. U.S. Pat. No. 5,610,271 discloses tetrapeptides containing four D-isomer amino acid residues that bind to KORs but do not exhibit all of these desirable characteristics.